ESR1 ligand-binding-domain hotspot Y537S or D538G — the two dominant hotspots (~70% of al...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-BREAST-ESR1-Y537S-D538G-CANDIDATE`
Type	Red flag
Status	reviewed 2026-04-29
Diseases	`DIS-BREAST`
Sources	`SRC-EMERALD-BIDARD-2022` `SRC-ESMO-BREAST-METASTATIC-2024` `SRC-NCCN-BREAST-2025`

Red Flag Origin

Definition	ESR1 ligand-binding-domain hotspot Y537S or D538G — the two dominant hotspots (~70% of all ESR1-LBD mutations) acquired in HR+/HER2- metastatic breast progressing on aromatase inhibitor. EMERALD (Bidard 2022) randomized post-AI ± CDK4/6i HR+ MBC to elacestrant vs endocrine standard-of-care; PFS benefit was concentrated in the ESR1-mutant subgroup (mPFS 3.8 vs 1.9 mo, HR 0.55). Y537S is associated with more aggressive biology than D538G in some series. Candidate RF refines RF-BREAST-ESR1-MUT-ACTIONABLE for the predominant hotspots specifically targeted by elacestrant data.
Clinical direction	intensify
Category	high-risk-biology

Trigger Logic

{
  "any_of": [
    {
      "finding": "esr1_y537s",
      "value": true
    },
    {
      "finding": "esr1_d538g",
      "value": true
    },
    {
      "finding": "esr1_hotspot",
      "value": "Y537S"
    },
    {
      "finding": "esr1_hotspot",
      "value": "D538G"
    },
    {
      "finding": "esr1_mutation",
      "value": "Y537S"
    },
    {
      "finding": "esr1_mutation",
      "value": "D538G"
    }
  ],
  "type": "biomarker"
}

Notes

Hotspot-specific narrowing of RF-BREAST-ESR1-MUT-ACTIONABLE. Y537S + D538G together account for ~70% of LBD mutations and are the hotspots most consistently represented in EMERALD subgroup analyses. Test on ctDNA at progression on AI ± CDK4/6i — preferred specimen due to subclonal + polyclonal nature of ESR1 mutations in tissue. Priority 67 sits between the broad ESR1-MUT-ACTIONABLE (70) and the AKT/PIK3CA family (65) — the engine should fire both this hotspot RF and the broader ESR1 RF when applicable; conflict resolution defers to clinical_direction (both intensify, no conflict). When ESR1-WT post-AI: elacestrant did not show benefit; switch to fulvestrant + capivasertib / alpelisib if PIK3CA / AKT1 / PTEN altered. EMERALD trial Source ingested (SRC-EMERALD-BIDARD-2022).

Used By

Indications

IND-BREAST-HR-POS-MAINT-CDK46I - IND-BREAST-HR-POS-MAINT-CDK46I
IND-BREAST-HR-POS-MET-1L-CDKI - IND-BREAST-HR-POS-MET-1L-CDKI